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United States Patent (19) 11) Patent Number: 4,861,760 Mazuel Et Al

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United States Patent (19) 11) Patent Number: 4,861,760 Mazuel Et Al United States Patent (19) 11) Patent Number: 4,861,760 Mazuel et al. (45) Date of Patent: Aug. 29, 1989 4,517,216 5/1985 Shim ..................................... 536/1.1 (54) OPHTHALMOLOGICAL COMPOSITION OF 4,563,366 l/1986 Baird et al. .. ... 426/573 THE TYPE WHICH UNDERGOES 4,638,059 1/1987 Sutherland ....... ... 536/123 LIQUID-GEL PHASE TRANSITION 4,661,475 4/1987 Bayerlein et al...................... 514/54 75 Inventors: Claude Mazuel; Marie-Claire 4,717,713 1/1988 Zatz et al. ............................. 514/54 Friteyre, both of Riom, France 4,746,528 5/1988 Prest et al. ........................... 536/1. 73) Assignee: Merck & Co., Inc., Rahway, N.J. FOREIGN PATENT DOCUMENTS 1072413 2/1980 Canada. (21) Appl. No.: 911,606 134649 3/1985 European Pat. Off. (22 Filed: Sep. 25, 1986 0142426 5/1985 European Pat. Off............. 514/914 30 Foreign Application Priority Data 1312244 6/1962 France . Oct. 3, 1985 (FR) France ................................ 85 14689 OTHER PUBLICATIONS 51) Int. Cl." .................... A61K 31/715; A61K 31/70 Jansson et al.; Carbohydrate Research vol. 124:135-139, 52 U.S.C. ...................................... 514/54; 514/912; (1983). 514/913; 514/915; 514/944; 536/1.1; 536/114; Crescenzi et al.; Carbohydrate Research, vol. 536/123 149:425-432, (1986). 58 Field of Search ................. 514/54,944, 912, 913, Primary Examiner-Ronald W. Griffin 514/915,954; 536/123, 114, 1.1 Assistant Examiner-Nancy S. Carson (56) References Cited Attorney, Agent, or Firm-William H. Nicholson; Joseph F. DiPrima U.S. PATENT DOCUMENTS 2,441,729 5/1948 Steiner ............ ... 514/944 57 ABSTRACT 2,935,447 5/1960 Miller et al. .......................... 514/54 The present invention relates to a pharmaceutical com 4,013,792 3/1977 Eichman et al. ... 574/171. position intended for contacting with a physiological 4,039,662 8/1977 Hecht et al. .......................... 514/54 4,136,173 1/1979 Pramoda et al. ... 514/800 liquid characterized in that said composition is intended 4,136,177 1/1979 Lin et al. ......... ... 514/913 to be administered as a non-gelled liquid form and is 4,188,373 2/1980 Krezanoski ........................... 514/11 intended to gel in situ, this composition containing at 4,326,052 4/1982 Kang et al. ... 536/123 least one polysaccharide in aqueous solution, of the type 4,326,053 4/1982 Kang et al. .. ... 536/123 which undergoes liquid-gel phase transition gelling in 4,343,787 8/1982 Katz ...................................... 514/54 situ under the effect of an increase in the ionic strength 4,407,792 10/1983 Schoenwald et al. .. ... 514/912 4,409,205 10/1983 Shively ................................. 514/53 of said physiological liquid. 4,474,751 10/1984 Haslam et al. ........................ 424/78 4,503,084 3/1985 Baird et al. ......................... 426/573 8 Claims, 1 Drawing Sheet U.S. Patent Aug. 29, 1989 4,861,760 O 13.5 54. 108 162 216 Sec FIG-1 FIG 2 4,861,760 1. 2 perature at physiological temperatures, which are of the OPHTHALMOLOGICAL COMPOSITION OF THE order of 25 C-36 C. TYPE WHICHUNDERGOES LIQUID-GEL PHASE Similarly, Canadian Patent No. 1,072,413 describes TRANSTION systems containing a therapeutic or other agent (polox amer), the gelification temperatures of which are made The present invention relates to a pharmaceutical higher than room temperature by using additives. composition containing at least one polysaccharide in The thermally gelling systems have many disadvan aqueous solution, of the type which undergoes liquid tages, including the risk of gelling before administration gel phase transition under the effect of an increase in the by an increase in the ambient temperature during pack ionic strength. 10 aging or storage, for example. The pharmaceutical compositions of the invention U.S. Pat. No. 4,474,751 of Merck & Co., relates to are of the type which undergoes liquid-gel phase transi other systems for delivering drugs based on ther tion under the effect of an increase in the ionic strength. mogelification of gels, but these systems require very They are particularly intended for contacting with large amounts of polymers and this is not always well physiological liquids. Thus the transition occurs at the 15 tolerated by the eye. contact, as the physiological liquids have a higher tonic The present invention relates to a pharmaceutical ity than the one of said compositions. composition intended for contacting with a physiolog The compositions of the invention are specially useful ical liquid characterized in that said composition is in for ophtalmic use, but also as injectable form, the tended to be administered as a non-gelled liquid form formed gel having thus the function of slow-release 20 and is intended to gel in situ, this composition contain form, as by intradermic or intramuscular injections, or ing at least one polysaccharide in aqueous solution, of as galenic form intended for contacting with mucous the type which undergoes liquid-gel phase transition membranes. gelling in situ under the effect of an increase in the ionic A large percentage of drugs administered to the eye is strength of said physiological liquid. lost as a result of lacrimal drainage; this applies espe 25 The prefered pharmaceutical composition according cially in the case of a liquid formulation. In effect, as a to the invention is an ophthalmological composition, result of this drainage, only a small fraction of the dose the physiological liquid being the lacrimal fluid. Thus, administered remains in contact with the cornea for a the present invention overcomes these particular prob few minutes, and an even smaller fraction penetrates 30 lems of administering ophthalmic compositions. into the eye. As a matter of fact, the composition, which takes the To overcome this disadvantage, it is known to use form of a liquid before its introduction into the eye, viscous solutions, gels, eye ointments or solid eye in undergoes a liquid-gel phase transition, and hence plants. changes from the liquid phase to the gel phase, once it Progress has been made in the delivery of drugs by 35 is introduced into the eye, as a result of the ionic the use of these galenical forms, especially by using the strength of the physiological fluid which is in this case, solid implants, by means of which it is possible to re the lacrimal fluid. duce greatly the doses of active principle in the formu This new ophthalmological composition is an amaz lation while retaining a therapeutic response equivalent ingly advantageous form for several reasons. In particu to that which would be induced by an eye lotion, the 40 lar, since the presence of lacrimal fluid is required to latter, in addition, needing to be administered more induce gel formation, any accidental spillage of solution frequently. outside of the eye cannot result in gel formation. Fur Some of these implants function by diffusion. Thus, thermore, in contrast to the thermally gelling systems, for example, in the “OCUSERT (R)' system, one an increase in the ambient temperature cannot result in weekly application of an oval lens in the conjunctival 45 the solution gelling during storage. sac enables an active principle to be delivered by diffu Also, the polymer used can form a gel at concentra sion, but this lens has to be removed after use, which is tions 10- to 100- fold lower than those used in systems a source of problems for the patients. involving thermogelification. It is hence very well tol Others function by dissolution, and, in this case, since erated by the eye. the implants are either soluble or autodegradable ("LA 50 Finally, when these compositions contain a pharma CRISERT (R)' system), their duration of action is much ceutically active substance, such a delivery system shorter. makes it possible to achieve great bioavailability of the In all cases, the solid implants possess a major disad product, and concentrations of active principle which vantage in that many patients find it difficult to tolerate are sustained with time, advantages of a slow delivery the introduction into the conjunctival culs-de-sacs of 55 system. the solid object represented by this implant. Furthermore, in the case of already gelled or semi To solve this problem, galenical forms can be used solid compositions, it is not possible to administer them which are liquid at room temperature and assure a semi by volumetric means, especially when they come from solid form at human body temperature. Such delivery a multi-dose container. To administer these in reproduc systems are described in U.S. Pat. No. 4,188,373, which 60 ible quantities, one is then compelled to employ gravi propose the use of "PLURONIC(R) polyols". metric means. These "PLURONIC(R) polyols" are thermally gel The compositions according to the invention have, ling polymers in which the polymer concentration is on the one hand, the advantage of liquid ophthalmic chosen in accordance with the desired liquid-gel transi compositions, namely reproducible and accurate dos tion temperature. 65 ing, by volumetric means, of the active substance, and However, with the commercially available on the other hand the advantages known for the systems "PLURONIC(R)polymers", it is difficult to obtain a gel in rigid or semisolid gel form, relating to the delivery of of suitable rigidity while maintaining the transition tem active substances. 4,861,760 3 4. The composition according to the invention conse The ophthalmic compositions according to the inven quently has neither the disadvantages of losses of active tion can be used as they are in various applications, and, substances characteristic of simple liquid compositions, for example, to maintain adequate hydration of the eye nor the unpleasant aspects of solid implant systems, nor (treatment of dry eye syndrome).
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    chromosome be active in a sufficient proportion of cells 9. Schwartz M, Yang HM, Niebuhr E, Rosenberg T, Page DC. in a tissue in which the gene is expressed then a female Regional localisation of polymorphic DNA loci on the proximal long arm of the X chromosome using deletions may manifest the disease in that tissue. If cells of only associated with choroideremia. Hum Genet 1988;78:156-60. parts of that tissue are affected then a mosaic pattern may 10. Van Bokhoven H, Van den Hurk JA, Bogerd L, Philippe C. be demonstrated. The X-inactivation ratio determines the Gilgenkrantz S, DeJong P, et al. Cloning and characterisation degree to which the tissue is affected and in our patient of the human choroideremia gene. Hum Mol Genet 1994;3:1041-6. could explain the laterality of involvement. 11. Lyon MF. Gene action in the X-chromosome of the mouse It might be argued that these changes are due to other (Mus musculus). Nature 1961;190:372. causes. Age-related macular degeneration is a possibility; 12. Jay B. X-linked retinal disorders and the Lyon hypothesis. however, the relatively early age of onset, paucity of Trans Ophthalmol Soc UK 1985;104:836-44. drusen and marked asymmetry of the macular findings 13. Flannery JG, Bird AC, Farber DB, Weleber RG, Bok D. A histopathologic study of a choroideremia carrier. Invest are somewhat atypical. Serpiginous choroiditis Ophthalmol Vis Sci 1990;31:229-36. commencing at and involving solely the macular region 14. Mansour AM, Jampol LM, Packo KH, Hrisomalos NF. has been described.l4,ls Involvement is bilateral, Macular serpiginous choroiditis.
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